Lack of Oncomodulin Increases ATP-Dependent Calcium Signaling and Susceptibility to Noise in Adult Mice

Dysregulation of Ca²⁺ homeostasis in cochlear outer hair cells (OHCs) is associated with impaired hearing following noise exposure. Ca²⁺ signaling in developing OHCs is modulated by oncomodulin (OCM), an EF-hand calcium-binding protein. Here, we investigated whether the lack of OCM disrupts Ca²⁺ signaling in mature OHCs and influences vulnerability to moderate noise. Using young adult CBA/CaJ mice of either sex, we found that OHCs from Ocm knock-out (Ocm^-/- ) mice showed comparable electromotile responses and synaptic innervation compared with littermate controls. Prior to noise exposure, Ocm ^-/- mice had auditory brainstem responses with highly variable latencies and amplitudes compared with Ocm ^+/+ mice. Moderate noise exposure (95 dB SPL, 2 h) caused temporary threshold shifts in wild-type (Ocm ^+/+) mice but PTS in Ocm ^-/- mice. Using a genetically encoded Ca²⁺ sensor (GCaMP6s) expressed in OHCs, we found increased GCaMP6s fluorescence and ATP-induced Ca²⁺ signaling in Ocm ^-/- OHCs. Using GCaMP6s mice of either sex, P2X2 expression was also higher throughout the cochlea of Ocm ^-/- mice compared with Ocm ^+/+ mice. Prolonged noise exposure (95 dB SPL, 9 h) led to greater threshold shifts in Ocm ^-/- mice and upregulated expression of P2X2 receptors in the cochlea of Ocm ^+/+ but not in the Ocm ^-/- mice. Prolonged noise exposure did not change the number of presynaptic OHC ribbons. We propose that the lack of OCM leads to a noise-exposed phenotype that increases susceptibility to cochlear pathology. Additionally, the combination of increased purinergic signaling and dysregulation of cytosolic Ca²⁺ homeostasis likely contributes to early-onset hearing loss in Ocm ^-/- mice.